Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesisof anabolic steroid action
a HPT/Axis Inc., 1660 Beaconshire Road, Houston, TX 77077, USAb OPAL Medical Clinic, 5555 West Loop S., Suite 205, Houston, TX 77401, USA
Anabolic steroid-induced hypogonadism (ASIH) is the functional incompetence of the testes with subnor-
mal or impaired production of testosterone and/or spermatozoa due to administration of androgens or
anabolic steroids. Anabolic–androgenic steroid (AAS), both prescription and nonprescription, use is a
cause of ASIH. Current AAS use includes prescribing for wasting associated conditions. NonprescriptionAAS use is also believed to lead to AAS dependency or addiction. Together these two uses account formore than four million males taking AAS in one form or another for a limited duration. While both ofthese uses deal with the effects of AAS administration they do not account for the period after AAS ces-sation. The signs and symptoms of ASIH directly impact the observation of an increase in muscle massand muscle strength from AAS administration and also reﬂect what is believed to demonstrate AASdependency. More signiﬁcantly, AAS prescribing after cessation adds the comorbid condition of hypogo-nadism to their already existing chronic illness. ASIH is critical towards any future planned use of AAS orsimilar compound to effect positive changes in muscle mass and muscle strength as well as an under-standing for what has been termed anabolic steroid dependency. The further understanding and treat-ments that mitigate or prevent ASIH could contribute to androgen therapies for wasting associateddiseases and stopping nonprescription AAS use. This paper proposes a uniﬁed hypothesis that the neteffects for anabolic steroid administration must necessarily include the period after their cessation orASIH.
Ó 2009 Elsevier Ltd. All rights reserved.
Another of the beliefs held by the medical community deals
with the period after anabolic steroid cessation, not their adminis-
The development of AAS compounds was originally for treat-
tration. The prevailing medical opinion is that clinically signiﬁcant
ment of hypogonadal dysfunction and commencement of delayed
ASIH occurs from nonprescription AAS use but not from clinically
puberty in men and for growth promotion AAS have, however,
prescribed AAS . The signs and symptoms of ASIH will neces-
not always been used for pure medical purposes. Due to their ana-
sarily impact upon our understanding for the clinical use of AAS.
bolic effects, AAS became vastly popular among athletes, body-
Additionally, these very same signs and symptoms might be
builders, and power lifters. Moreover, scientiﬁc and ofﬁcial court
instrumental in what has been described as AAS dependency.
documents, including doctoral theses and scientiﬁc reports, dem-onstrate the positive effects of these and other hormonal drugs on
Anabolic steroid-induced hypogonadism (ASIH)
muscle strength and performance in elite sports, which was com-mon knowledge and had been in practice since the early 1960s .
Anabolic–androgenic steroids (AAS) are a class of compounds
Controversy raged for decades over the effectiveness of AAS in
that include any drug or hormonal substance, chemically and phar-
promoting muscle mass and muscle strength. Despite the admitted
macologically related to testosterone that stimulates the growth or
illicit use of AAS by athletes, the record breaking in Olympic events,
manufacturing of bone and muscle. It has long been held that non-
and the obvious appearance in musculature enhancement, the
prescription AAS use results in a functional type of hypogonadotro-
medical and research community disputed and denied the AAS ef-
pic hypogonadism. Boje was the ﬁrst physician to suggest, in 1939,
fects . After a considerable period of scientiﬁc controversy, it is
that AAS might enhance athletic performance, but he was also the
now clear that anabolic–androgenic steroid hormones are effective
ﬁrst to forewarn athletes of potential health effects of steroids.
in increasing both muscle mass and muscle strength .
For over a quarter century, publications demonstrate HPTA sup-
pression after nonprescription anabolic steroid use. Consistently,there is found a dramatic suppression of serum gonadotropins
* Corresponding author. Tel.: +1 281 493 4817; fax: +1 713 490 3543.
and testosterone levels that continues for an indeﬁnite period after
0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2008.12.042
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042
R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx
AAS cessation . In 2003, a retrospective study examined the
ure to AAS, with the signs and symptoms after AAS cessation indi-
effects of illicit AAS on a population in which the mean time off ste-
cations of AAS withdrawal . Upon nonprescription AAS
roids was 43 months with the minimum length of time 1 year and
cessation, psychological disturbances include aggressiveness,
the maximum 10 years. The study found 13/15 ex-AAS users were
depression, anxiousness, potency problems (libido), sleep disor-
in the lower 20 percent of the normal reference range for testoster-
ders, violent behavior, rage, and suicidal ideation
one and 2/15 were below the normal range . Another well-de-
The two most widely-accepted standards for deﬁning, classify-
scribed event are reports citing long periods for the return of
ing and diagnosing drug abuse and dependence are the Diagnostic
spermatogenesis after nonprescription AAS use, include continuing
Statistical Manual IV (DSM-IV) and the International Classiﬁcation
azoospermia . Contrary to the belief that nonprescription
of Diseases, Volume 10 (ICD-10). The Diagnostic Statistical Manual
AAS doses are 10–100-fold greater than those clinically prescribed,
IV (DSM-IV) and the International Classiﬁcation of Diseases, Vol-
reports include doses approximately twice that for replacement
ume 10 (ICD-10) differ in the way they regard anabolic–androgenic
steroids’ (AAS) potential for producing dependence . DSM-IV
Similarly, during the same timeframe documentation in peer-
regards AAS as potentially dependence producing and ICD 10 re-
reviewed literature shows AAS prescribing with clinical doses
gards them as non-dependence producing.
and durations to cause both gonadotropin suppression and de-
This difference in approach towards AAS prompts debate as to
creased serum testosterone after AAS cessation The
whether or not AAS are dependence-producing substances. The
authors went so far as to warn that anabolic steroid administration
main work in this area has been conducted by Brower et al.
is a possible cause for hypogonadism Birth control studies
who investigated the existence of a ‘‘steroid
with testosterone administration in physiological as well as sub-
dependency syndrome” and classiﬁed subjects as dependent on
physiological doses demonstrate HPTA suppression and continuing
AAS using an adaptation of the DSM-III-R criteria for depen-
infertility . More recent studies and reviews on androgen
dence on psychoactive substances, which differ only slightly from
and androgen/progestin male contraceptives conﬁrm the offset of
reliable contraception and of resumption of normal male fertility
In 2002, Brower summarizes the literature on AAS abuse and
to baseline values can be up to 2 years Finally, even the
dependence and reports of at least 165 cases of addiction or depen-
FDA approved labeling PDR for AAS contain the adverse effects of
dence in the medical literature Brower also concludes no cases
HPTA suppression, inhibition of testicular function, testicular atro-
of dependence have been associated with legitimate prescriptions
phy, oligospermia, impotence, and more.
of AAS used at therapeutic doses for medical purposes. According
Published literature uniformly ﬁnds AAS administration, both
to Brower, individuals who use high doses of AAS over prolonged
prescription and nonprescription, induces a state of hypogonadism
periods may develop withdrawal symptoms that include fatigue,
after AAS cessation. All compounds classiﬁed as anabolic–andro-
depressed mood, restlessness, anhedonia, impaired concentration,
genic steroids cause a negative feedback inhibition of the hypotha-
increased aggression, anorexia, insomnia, decreased libido, self-im-
lamic pituitary testicular axis, suppress endogenous gonadotropin
age dissatisfaction, androgen desire, headaches, suicidal ideation,
secretion, and as a consequence endogenous testosterone produc-
decrease in size/weight/strength, and feeling depressed/down/un-
tion. After AAS administration, HPTA suppression follows, with the
happy due to size loss when they stop taking AAS and these with-
variables being the duration and severity.
drawal effects may contribute to a syndrome of dependence. As the
ASIH, as a form of hypogonadism, is a real disease with poten-
table shows below, the patient with hypogonadism may experi-
tially serious consequences. Declining, or suppressed, circulating
ence almost all of these above symptoms . Rather than diag-
testosterone levels because of either pathophysiological or induced
nosing substance abuse or dependence the criteria in use by
hypogonadal conditions can have many negative consequences in
these investigators for addiction is the patient examination for
males. There is an association between hypogonadism (decreased
levels of testosterone) and a number of signs and symptoms, mostnotably body composition changes (decrease in muscle mass and
Symptoms of hypogonadism vs. dependence.
increase in fat mass), decreased muscle strength, bone loss, in-creased cardiovascular risk, sexual dysfunction (decreased libido,
decreased spontaneous erections, decreased ejaculate, erection
dysfunction, decreased sexual fantasies, and anorgasmia), de-
creased cognitive abilities (memory and concentration), sleep dis-
turbances, adverse psychological effects (depression, low-self
esteem, guilt, increased stress, and anhedonia), and constitutional
symptoms (general fatigue, agitation/motor dyskinesia, and de-
creased appetite) . These adverse effects have importance in
an understanding for what has been called AAS dependency and
the clinical use in wasting associated conditions of AAS for positive
changes in muscle mass and muscle strength.
The association of AAS with adverse psychological and behav-
ioral effects is extensive . Historically, researchers went
so far as to categorically state that AAS are without any evidence
upon muscle going so far as to argue that there is saturation of
the androgen receptor with eugonadal levels of testosterone. This
attitude spurned the concept that the large doses commonly used
by illicit AAS users indicate that the drug use is for actions other
than their normal physiological effects, implying an addictive nat-
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042
R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx
verse muscle wasting and augment muscle function may reduce
the burden of disease, improve quality of life, and reduce utiliza-
tion of health care resources. Because of the effects of testoster-
one in enhancing lean body mass (LBM), muscle strength, and
decreased adiposity studies investigate the possible role for tes-
tosterone or anabolic–androgenic steroids (AAS) in catabolic
states. Anabolic–androgenic steroids have received particular
attention with regard to improving body composition in those
The current prescribing of AAS, including testosterone, is for
sarcopenia (loss of muscle mass and muscle strength with ageing),chronic kidney disease (hemodialysis), HIV+ males, chronic
In 1990, the National Institute of Drug Abuse (NIDA) published an
obstructive pulmonary disease (COPD), osteoporosis, and long-
extensive monograph on anabolic steroid abuse This mono-
term glucocorticoid treatment The anabolic steroid re-
graph represents a ‘‘state-of-the-art” information resource concern-
search concludes that anabolic steroid administration results in-
ing anabolic steroid abuse. ‘‘It must be concluded at this time that
creases in muscle mass and muscle strength. Based on these
the use of steroids by humans does not meet the criteria necessary
conclusions, the physician-investigators recommend their use as
to establish that steroids have signiﬁcant abuse liability as deﬁned
a possible means of decreasing morbidity and mortality. These
in pharmacological terms”. The conclusion from this monograph is
studies are indicative of the developing trend in using aggressive
anabolic steroids do not satisfy the criteria for abuse potential.
pharmacological therapy with anabolic steroids to reverse declines
Echoing this opinion is a report from President’s Council on Physical
in lean body mass and muscle strength. On close inspection of
Fitness. In 1994, evidence review of the published literature states,
these investigations where there is measurement of sex hormones
‘‘Despite increasing clinical descriptive data on anabolic steroid
or documentation of side-effects there is the universal ﬁnding of
withdrawal, dependence, and abuse, there are insufﬁcient substan-
tial basic or clinical research data to support the inclusion of these
In all of the studies that include muscle mass and muscle
syndromes in DSM-IV” . In the intervening 18 years since the
strength measurements both during and after AAS administration,
original ﬁndings, there is nothing in the published scientiﬁc litera-
the positive effects of AAS during their administration disappear in
ture to change these conclusions. There are few, if any, well-con-
the period after stopping AAS . In 2004, after years of pub-
trolled investigations or studies on the dependence potential of
lished studies reporting on the positive beneﬁts of AAS administra-
tion but with no follow-up for the period of hypogonadism after
In the future, studies on AAS dependency must include for the
AAS cessation a randomized controlled study reported on the body
monitoring of hypogonadism. This paper proposes that these trials
composition changes during administration and after a 12-week
will support and afﬁrm the hypothesis that the signs and symp-
follow-up period after AAS cessation The study found that
toms previously attributed to dependency will be due to ASIH. Fur-
the positive body composition changes in lean body mass, muscle
ther, treatments aimed at preventing or mitigating ASIH will prove
area, and strength produced by the androgen in the study had com-
pletely disappeared 12 weeks after AAS cessation. Rather than rec-ognize anabolic–androgenic steroid-induced hypogonadism as thecritical factor for the loss of muscle mass and strength, these inves-tigators suggest, ‘‘However, the beneﬁts were lost within 12 weeks
after oxandrolone was discontinued, suggesting that prolongedandrogen treatment would be needed to maintain these anabolic
The idea that secretions of the testis might regulate body
composition is as old as humanity itself. For decades, testoster-
Each of the aforementioned studies examined the effects of AAS
one and testosterone analogues, anabolic–androgenic steroids
during their administration. Upon discontinuation of AAS, these
(AAS), have long been used in the athletic community for
patients would develop anabolic steroid-induced hypogonadism
improving muscle mass and muscle strength. Despite the obvi-
(ASIH), which negates the positive body composition changes
ous changes in musculature and appearance to even the most
and potentially leave them in a state of health worse than when
uninitiated, the academic community steadfastly refused to ad-
ﬁrst prescribed AAS. These studies utilizing AAS therapy have not
mit to any association. The scientiﬁc evidence shows the con-
identiﬁed what should be done to restore normal endocrine status
post-treatment. The most signiﬁcant concern is that marginally
In 1996, Bhasin et al. reported testosterone administration
healthy individuals placed on AAS for this goal may be placing
causes an increase in muscle mass and muscle strength .
themselves at an even greater morbidity and mortality risk upon
The investigation is not a clinical study for AAS treatment, but
a study to separate out the effects of progressive resistance exer-
Interestingly, nonsteroidal androgen or selective androgen
cise and AAS on muscle mass and strength. Signiﬁcantly, the re-
receptor modulators (SARM) administration is currently in the re-
search did not include the period after anabolic steroid
search and investigational stages for the same purposes as ana-
administration. In spite of the known effects of AAS upon the
bolic steroids. These studies indicate that their clinical use will
HPTA, the evolution of AAS treatments for their ability to in-
result in induced hypogonadism after cessation by their effects
crease muscle mass and improve muscle strength began in ear-
on gonadotropin levels This same opinion was voiced by
investigators that, ‘‘Selectivity with regard to gonadotropin sup-
In many chronic illnesses, we can now achieve disease stability
pression represents a signiﬁcant barrier to the clinical use of
but not cure. In these chronic disorders, loss of muscle occurs fre-
quently and is associated with debility, impaired quality of life,
This does not mean that the use of androgens to promote posi-
and poor disease outcome. Similarly, as men grow older, their
tive changes in muscle mass and muscle strength needs to be aban-
muscle mass decreases and fat mass increases in association with
doned. The better approach is to develop combinatorial therapies
a decline in testosterone levels. Therefore, strategies that can re-
of androgens for an improvement in muscle mass and muscle
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042
R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx
strength followed by a treatment to prevent or minimize ASIH,
thereby sustaining those positive changes.
There are reports of the use of anabolic steroids by athletes
since the 1950s to increase muscle size and strength to improve
performance. Anabolic steroids use became more prominent inthe athletic world, but use by the lay public has also increased.
A treatment goal of HPTA restoration will have its basis in the
Long conﬁned to bodybuilding and professional sports, the use of
regulation and control of testosterone production. The HPTA has
AAS is nowadays a problem that involves a wider population. In
two components, both spermatogenesis and testosterone produc-
2006, a report demonstrates that AAS use is common among males
tion. In males, luteinizing hormone (LH) secretion by the pituitary
over 18 years In the United States, prevalence estimates are
positively stimulates testicular testosterone (T) production; folli-
between 4% and 12% among adolescent males . Current esti-
cle-stimulating hormone (FSH) stimulates testicular spermatozoa
mates from 2000 indicate that there are as many as three million
production. The pulsatile secretion of gonadotropin-releasing hor-
AAS users in the United States and that 2.7–2.9% of adults have ta-
mone (GnRH) from the hypothalamus stimulates LH and FSH
ken AAS at least once in their lives According to surveys
secretion. In general, absent FSH, there is no spermatozoa produc-
and media reports, the illegal use of these drugs to increase muscle
tion; absent LH, there is no testosterone production. Regulation of
the secretion of GnRH, FSH, and LH occurs partially by the negative
Anabolic–androgenic steroids are now commonly a prescribed
feedback of testosterone and estradiol at the level of the hypothal-
drug for chronic illnesses, with estimates in the millions
amo-pituitary. Estradiol has a much larger, inhibitory effect than
. AAS treatment for these conditions is towards disease-asso-
testosterone, being 200-fold more effective in suppressing LH
ciated morbidity, decreased muscle mass and decreased muscle
strength, not treatment for the underlying disease cause. The treat-
In the case of ASIH, where the individual suffers from functional
ment for these conditions is of a limited duration. In addition, ad-
hypogonadism and the belief for eventual return of function, treat-
verse effects necessitate and require the discontinuation of these
ment is directed at HPTA restoration. A medical quandary for phy-
drugs. While the anecdotal and research reports of AAS beneﬁts
sicians presented with hypogonadal patients secondary to AAS
are inarguable, there is the real problem for failure to consider the
administration is there is currently no FDA approved drug to re-
period after their cessation, anabolic steroid-induced hypogonadism
store HPTA function. Standard treatment to this point has been tes-
Clinical application of published study results is dependent
gonadotropin (hCG), conservative therapy (‘‘watchful waiting” or
upon sound research design. In these studies, the intervention,
‘‘do nothing”), or off-label prescribing of aromatase inhibitors or
AAS, causes a change in the prognosis in the treatment group. This
selective estrogen receptor modulators (SERM).
introduces bias, making the conclusions invalid. Biased research
The primary drawback of testosterone replacement and hCG
results open the door for harm to patients extending far beyond
administration is that this therapy is inﬁnite in nature. These treat-
those subjects involved in the clinical trial. These results may lead
ments will remedy the signs and symptoms associated with hypo-
to erroneous conclusions about the safety or the efﬁcacy of drugs.
gonadism, but do not alleviate the need for a life-long commitment
Researchers working on the next generation of research, creating a
to therapy. Further, administration serves to further HPTA suppres-
domino effect of error, will also use them. Once disseminated in
sion. Conservative therapy (‘‘watchful waiting” or ‘‘do nothing”) is
the market, end user physicians and patients will pay the price
the probably worst case option as this does nothing to treat the pa-
for bad science in dollars, poor outcomes, and adverse events .
tient with ASIH. Also, conservative therapy will have the undesir-
Importantly, a ‘‘good question” can be approached by good or
able result of the nonprescription AAS user to return to AAS use
bad research techniques; bad research methods do not render
as a means to avoid ASIH signs and symptoms.
the question valueless. Thus, the signiﬁcance of a hypothesis can
The aromatase inhibitors demonstrate the ability to cause an
and should be assessed prior to and independent of the speciﬁc re-
elevation of the gonadotropins and secondarily serum testosterone
search methods. Reviewers should not dismiss a proposal that uses
. The administration of SERMs is a common treatment in at-
inadequate methods without ﬁrst considering whether adjust-
tempts to restore the HPTA because they increase LH secretion
ments could make the proposal scientiﬁcally valid.
from the pituitary that leads to increased local testosterone pro-
Without deﬁnitive studies demonstrating there is no clinical con-
sequence to ASIH after both prescription and nonprescription use,
Guay has used clomiphene citrate as therapy for erection dys-
the understanding of AAS actions will be incomplete. Any hypothesis
function and secondary hypogonadism. Patients received clomi-
on AAS in health and disease requires a thorough understanding for
phene citrate 50 mg per day for 4 months in an attempt to raise
the action not only during administration but also after their cessa-
their testosterone level . Clomiphene has been reported in a
tion. This paper proposes that clinically signiﬁcant anabolic steroid-
case study to reverse andropause secondary to anabolic–andro-
induced hypogonadism (ASIH) ensues for both illicit and licit AAS
genic steroid use The patient received clomiphene citrate
use after AAS cessation with the severity and duration unknown.
50 mg twice per day in an attempt to raise his testosterone level.
Moreover, treatments that mitigate or prevent ASIH will be use-
The patient when followed up after two months had a relapse,
ful not only in the treatment for the adverse psychological effects
tiredness and loss of libido, after discontinuing clomiphene citrate.
after stopping AAS, but also when used in combination with andro-
There are case study reports demonstrating the effectiveness of
gens to aid in the maintenance or sustaining of anabolic improve-
the combination of clomiphene and tamoxifen in HPTA restoration
ments sought in disorders marked by wasting. Finally, ASIH
after stopping AAS administration Clomiphene is a mix-
treatments might prove beneﬁcial in mitigation of future post male
ture of the trans (enclomiphene) and cis (zuclomiphene) enantio-
contraceptive infertility. These need to be followed up with well-
mers, which have opposite effects upon the estradiol receptor
. Enclomiphene is an estradiol antagonist, while zuclomipheneis an estradiol agonist. The addition of tamoxifen to clomiphene
might be expected to increase the overall antagonism of the estra-
[1] Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138: anabolic–androgenic
diol receptor. Enclomiphene alone might be a good candidate to re-
steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042
R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx
[2] Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a
[34] Brower KJ, Eliopulos GA, Blow FC, Catlin DH, Beresford TP. Evidence for
secret program of the German Democratic Republic Government. Clin Chem
physical and psychological dependence on anabolic androgenic steroids in
eight weight lifters. Am J Psychiatry 1990;147(4):510–2.
[3] Wilson JD. Androgen abuse by athletes. Endocr Rev 1988;9:181–99.
[35] Hays LR, Littleton S, Stillner V. Anabolic steroid dependence. Am J Psychiatry
[4] Elashoff JD, Jacknow AD, Shain SG, Braunstein GD. Effects of androgenic–
anabolic steroid on muscle strength. Ann Intern Med 1991;115:387–93.
[36] Brower KJ, Blow FC, Beresford TP, Fuelling C. Anabolic–androgenic steroid
[5] Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of
dependence. J Clin Psychiatry 1989;50:31–3.
testosterone on muscle size and strength in normal men. N Engl J Med
[37] Brower KJ, Blow FC, Young JP, Hill EM. Symptoms and correlates of anabolic–
androgenic steroid dependence. Br J Addict 1991;86:759–68.
[6] Knuth UA, Maniera H, Nieschlag E. Anabolic steroids and semen parameters in
[38] Brower KJ, Blow FC, Eliopulos GA, Beresford TP. Anabolic androgenic steroids
bodybuilders. Fertil Steril 1989;52:1041–7.
and suicide. Am J Psychiatry 1989;146:1075.
[7] Brower KJ. Anabolic steroid abuse and dependence. Curr Psychiatry Rep
[39] Eklof AC, Thurelius AM, Garle M, Rane A, Sjoqvist F. The anti-doping hot-line, a
means to capture the abuse of doping agents in the Swedish society and a new
[8] Clerico A, Ferdeghini M, Palombo C, et al. Effect of anabolic treatment on the
serum levels of gonadotropins, testosterone, prolactin, thyroid hormones and
myoglobin of male athletes under physical training. J Nucl Med Allied Sci
[40] Midgley SJ, Heather N, Davies JB. Dependence-producing potential of
anabolic–androgenic steroids. Addict Res 1999;7(6):539–50.
[9] Ruokonen A, Alen M, Bolton N, Vihko R. Response of serum testosterone and its
[41] Brower KJ. Addictive potential of anabolic steroids. Psychiatric Ann
precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-
administration in man. J Steroid Biochem 1985;23:33–8.
[42] Brower K. Anabolic steroids: addictive, psychiatric and medical consequences.
[10] Alen M, Hakkinen K. Physical health and ﬁtness of an elite bodybuilder during
1 year of self-administration of testosterone and anabolic steroids: a case
[43] American Psychiatric Association. Diagnostic and statistical manual of mental
study. Int J Sports Med 1985;6:24–9.
disorders. Revised. 3rd ed. Washington, DC: American Psychiatric Association;
[11] Urhausen A, Torsten A, Wilfried K. Reversibility of the effects on blood cells,
lipids, liver function and hormones in former anabolic–androgenic steroid
[44] American Psychiatric Association. DSM-IV draft criteria, 3/1/93. Washington,
abusers. J Steroid Biochem Mol Biol 2003;84:369–75.
DC: American Psychiatric Association; 1993. The nine adapted DSM-III-R
criteria for psychoactive substance dependence are (1) more substance taken
hypogonadism. Am J Sports Med 1990;18:429–31.
than intended, (2) desire yet unable to cut down or control use, (3) large time
[13] Gazvani MR, Buckett W, Luckas MJ, Aird IA, Hipkin LJ, Lewis-Jones DI.
expenditure on substance related activity, (4) frequent intoxication or
Conservative management of azoospermia following steroid abuse. Hum
withdrawal symptoms when expected to function or when physically
hazardous, (5) social, work, or leisure activities replaced by AAS use., (6)
[14] Maeda Y, Nakanishi T, Ozawa K, et al. Anabolic steroid-associated
continued AAS use despite problems caused or worsened by use, (7) tolerance,
hypogonadism in male hemodialysis patients. Clin Nephrol 1989;32:198–201.
(8) withdrawal symptoms, and (9) substance used to relieve or avoid
nandrolondecanoate on the pituitary–gonadal axis in males. Acta Endocrinol
[45] Anabolic steroid abuse. NIDA Res Monogr 1990;102:1–241.
[46] Tsuang JW. Anabolic steroids withdrawal, dependence, and abuse. In: DSM-IV
[16] Shefﬁeld-Moore M, Urban RJ, Wolf SE, et al. Short-term oxandrolone
sourcebook. American Psychiatric Publishing Inc.; 1994.
administration stimulates net muscle protein synthesis in young men. J Clin
[47] Bhasin S, Storer TW, Javanbakht M, Berman N, Yarasheski KE, Phillips J, et al.
Testosterone replacement and resistance exercise in HIV-infected men with
[17] Contraceptive efﬁcacy of testosterone-induced azoospermia in normal men.
weight loss and low testosterone levels. JAMA 2000;283:763–70.
World Health Organization Task Force on methods for the regulation of male
[48] Grinspoon S, Corcoran C, Parlman K, Costello M, Rosenthal D, Anderson E, et al.
Effects of testosterone and progressive resistance training in eugonadal men
[18] Schurmeyer T, Knuth UA, Belkien L, Nieschlag E. Reversible azoospermia
with AIDS wasting. A randomized, controlled trial. Ann Intern Med
induced by the anabolic steroid 19-nortestosterone. Lancet 1984;1:417–20.
[19] Ly LP, Liu PY, Handelsman DJ. Rates of suppression and recovery of human
[49] Sattler FR, Jaque SV, Schroeder ET, Olson C, Dube MP, Martinez C, et al. Effects
sperm output in testosterone-based hormonal contraceptive regimens. Hum
of pharmacological doses of nandrolone decanoate and progressive resistance
training in immunodeﬁcient patients infected with human immunodeﬁciency
[20] Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C. Rate, extent,
virus. J Clin Endocrinol Metab 1999;84:1268–76.
and modiﬁers of spermatogenic recovery after hormonal male contraception:
[50] Schroeder ET, Singh A, Bhasin S, Storer TW, Azen C, Davidson T, et al. Effects of
an integrated analysis. Lancet 2006;367(9520):1412–20.
an oral androgen on muscle and metabolism in older, community-dwelling
[21] Testosterone: action, deﬁciency, substitution. In: Nieschlag E, Behre HM,
men. Am J Physiol Endocrinol Metab 2003;284:E120–8.
editors. Berlin Heidelberg: Springer-Verlag; 1998.
[51] Strawford A, Barbieri T, Neese R, Van Loan M, Christiansen M, Hoh R, et al.
[22] Allnutt S, Chaimowitz G. Anabolic steroid withdrawal depression: a case
Effects of nandrolone decanoate therapy in borderline hypogonadal men with
report. Can J Psychiatry 1994;39:317–8.
HIV-associated weight loss. J Acquir Immune Deﬁc Syndr Hum Retrovirol
[23] Bahrke M, Wright J, Strauss R, Catlin D. Psychological moods and subjectively
[52] Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral
androgenic steroid use. Am J Sports Med 1992;20:717–24.
testosterone supplementation increases muscle and decreases fat mass in
[24] Bahrke MS, Wright JE, O’Connor JS, Strauss RH, Catlin DH. Selected
healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci
psychological characteristics of anabolic–androgenic steroid users. N Engl J
[53] Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body
[25] Williamson DJ, Young AH. Psychiatric effects of androgenic and anabolic–
composition induced by testosterone and reversal of changes after drug is
androgenic steroid abuse in men: a brief review of the literature. J
[54] Schroeder ET, Zheng L, Yarasheski KE, et al. Treatment with oxandrolone
[26] Pope HG, Katz DL. Psychiatric and medical effects of anabolic–androgenic
steroid use: a controlled study of 160 athletes. Arch Gen Psychiatry
[55] Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen
[27] Pope HG, Kouri EM, Hudson JI. Effects of supraphysiologic doses of
receptor modulator is efﬁcacious on bone, muscle, and sex function with
testosterone on mood and aggression in normal men. Arch Gen Psychiatry
reduced impact on prostate. Endocrinology 2007;148:363–73.
[56] Gao W, Dalton JT. Ockham’s razor and selective androgen receptor modulators
[28] Kouri EM, Lukas SE, Pope HG, Oliva PS. Increased aggressive responding in
(SARMs): are we overlooking the role of 5{alpha}-reductase? Mol Interv
male volunteers following the administration of gradually increasing doses of
testosterone cypionate. Drug Alcohol Depend 1995;40:73–9.
[57] Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley F. Aromatase inhibition
[29] Lefavi RG, Reeve TG, Newland MC. Relationship between anabolic steroid use
in the human male reveals a hypothalamic site of estrogen feedback. J Clin
and selected psychological parameters in male bodybuilders. J Sport Behav
[58] Bagatell CJ, Dahl KD, Bremner WJ. The direct pituitary effect of testosterone to
[30] O’Connor DB, Archer J, Wu FC. Effects of testosterone on mood, aggression, and
inhibit gonadotropin secretion in men is partially mediated by aromatization
sexual behavior in young men: a double-blind, placebo-controlled, cross-over
to estradiol. J Androl 1994;15:15–21.
study. J Clin Endocrinol Metab 2004;89(6):2837–45.
[59] Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley WF. Sex steroid control of
[31] Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, Rubinow DR.
Neuropsychiatric effects of anabolic steroids in male normal volunteers.
administration in normal and gonadotropin-releasing hormone-deﬁcient
men. J Clin Endocrinol Metab 1991;73:621–8.
[32] Choi PYL, Parrott AC, Cowan D. High-dose anabolic steroids in strength
[60] Veldhuis JD, Dufau ML. Estradiol modulates the pulsatile secretion of
athletes: effects upon hostility and aggression. Hum Psychopharmacol
biologically active luteinizing hormone in man. J Clin Invest 1987;80:631–8.
[61] Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone’s short-
[33] Kashkin KB, Kleber HD. Hooked on hormones? An anabolic steroid addiction
term feedback restraint of 24-h endogenously driven and acute exogenous
hypothesis. JAMA 1989;262:3166–70.
gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042
R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx
stimulating hormone secretion in young men. J Clin Endocrinol Metab
HIV+ male with secondary polycythemia treated 2 years continuously with
testosterone. Endocrine Practice 2003;9(Suppl. 1).
[62] Roth MY, Amory JK, Page ST. Treatment of male infertility secondary to morbid
[71] Vergel N, Hodge AL, Scally MC. HPGA normalization protocol after androgen
obesity. Nat Clin Pract Endocrinol Metab 2008;4(7):415–9.
treatment. In: 4th international workshop on adverse drug reactions and
[63] Naftolin F, Judd HL, Yen SSC. Pulsatile patterns of gonadotropins and
lipodystrophy in HIV. Antiviral Therapy 2002;7:L53.
testosterone in man: the effects of clomiphene, with and without
[72] Scally MC, Street C, Hodge A. Androgen induced hypogonadotropic
testosterone. J Clin Endocrinol Metab 1973;36:285–8.
hypogonadism: treatment protocol involving combined drug therapy. The
[64] Winters SJ, Troen P. Evidence for a role of endogenous estrogen in the
Endocrine Society 2001 Annual Meeting. Denver, CO [Abstract].
hypothalamic control of gonadotropin secretion in men. J Clin Endocrinol
[73] Street C, Scally MC. Pharmaceutical intervention of anabolic steroid induced
hypogonadism – our success at restoration of the HPG axis. Med Sci Sports
[65] Winters SJ, Janick JJ, Loriaux DL, Sherins RJ. Studies on the role of sex steroids
in the feedback control of gonadotropin concentrations in men. II. Use of the
[74] Turner RT, Evans GL, Sluka JP, et al. Differential responses of estrogen target
zuclomiphene. Endocrinology 1998;139(9):3712–20.
[66] Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA. Short- and long-term
[75] Parkinson AB, Evans NA. Anabolic androgenic steroids: a survey of 500 users.
effects of clomiphene citrate on the pituitary–testicular axis. J Clin Endocrinol
Med Sci Sports Exerc 2006;38:644–51.
[76] Buckley WE, Yesalis 3rd CE, Friedl KE, Anderson WA, Streit AL, Wright JE.
[67] Gooren LJ, Van der Veen EA, van Kessel H, Harmsen-Louman W. Estrogens in
Estimated prevalence of anabolic steroid use among male high school seniors.
the feedback regulation of gonadotropin secretion in men: effects of
administration of estrogen to agonadal subjects and the antiestrogen
[77] National Institute on Drug Abuse (NIDA). About anabolic steroid abuse. NIDA
tamoxifen and the aromatase inhibitor d1-testolactone to eugonadal
subjects. Andrologia 1984;16:568–77.
[78] Irving LM, Wall M, Neumark-Sztainer D, Story M. Steroid use among
[68] Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Clomiphene increases
adolescents: ﬁndings from project EAT. J Adolesc Health 2002;30:243–52.
free testosterone levels in men with both secondary hypogonadism and
[79] Evans NA. Current concepts in anabolic–androgenic steroids. Am J Sports Med
erectile dysfunction: who does and does not beneﬁt? Int J Impot Res
[80] Perls TT, Reisman NR, Olshansky SJ. Provision or distribution of growth
[81] Kuszler PC. Conﬂicts of interest in clinical research: legal and ethical issues:
[70] Scally MC, Kovacs JA, Gathe JC, Hodge AL. Uncontrolled case study of medical
curing conﬂicts of interest in clinical research: impossible dreams and harsh
treatment for elimination of hypogonadism after androgen cessation in an
realities. Wid L Symp J 2001;8:115–52.
Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a uniﬁed hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042